The rhesus macaque infected with the simian immunodeficiency virus (SIV) is the premier animal model for the study of AIDS pathogenesis in general and of the neuropathogenesis of AIDS in particular. In addition, nonhuman primates are widely used in neuroscience research including neurophysiologic and neurobehavioral studies. In this proposal we will leverage existing data and expertise in these two important areas for a translational research program to examine the possible effects of substance P and its antagonists on AIDS pathogenesis. The proposal will further synergize with expertise of our collaborators on this IPCP with SP and its antagonists. The broad goals of this study are to: 1) determine the association between SIV disease progression, SP level, and indices of psychological disturbance and 2) identify mechanisms whereby SP or Neurokinin-1 receptor (NK1R) antagonists affect SIV disease progression. Our overall hypothesis is that SP production is increased in SIV infected macaques and that NK1R antagonists which target the SP receptor will have a protective effect on SIV disease progression and neurobehavioral parameters by 1) decreasing SIV replication in monocyte/macrophages, particularly perivascular macrophages in the central nervous system (CNS) and 2) blocking the known neurobehavioral effects of SP. To address our goals and this hypothesis we propose the following specific aims: Aim 1) Determine the cellular distribution of SP and its receptor in tissues of normal and SIV-infected macaques at various stages of disease. Aim 2) Characterize the natural history of SP in normal and SIV-infected rhesus macaques in relation to viral, i mmunologic, circadian and behavioral measures. Aim 3) Examine the effect of NK1R antagonists in normal and SIV-infected macaques.